PNPLA6 – Hereditary Spastic Paraplegia Type 39

Biallelic PNPLA6 variants have been reported in a single sibship presenting with early‐onset lower limb spasticity, weakness and ataxia consistent with Hereditary Spastic Paraplegia type 39 (HSP39). Three siblings carrying the homozygous c.3304G>A (p.Ala1102Thr) variant were affected from childhood ([PMID:32623594]), with segregation in two additional affected relatives. Two siblings developed dopa-responsive parkinsonian features and a positive dopamine transporter scan in middle age, expanding the HSP39 phenotypic spectrum to include extrapyramidal manifestations. No additional unrelated probands have been described to date.

Functional studies in a Drosophila sws1 null model demonstrate that wild-type human PNPLA6 rescues locomotor defects and normalizes lipid levels, whereas the c.1544T>C (p.Leu515Pro) and c.3266G>A (p.Arg1089Gln) mutant proteins fail to restore phospholipid homeostasis despite partial behavioral rescue ([PMID:31780887]). These results support a loss-of-function mechanism for disease-causing PNPLA6 alleles. Overall, genetic evidence remains limited, relying on a single family, but functional concordance in vivo lends moderate experimental support. Additional unrelated cases and segregation data are needed to elevate the clinical validity. Clinically, screening for PNPLA6 variants should be considered in early‐onset spastic paraplegia, especially when extrapyramidal signs emerge.

References

• Journal of neurology • 2020 • Bi-allelic variants in PNPLA6 possibly associated with Parkinsonian features in addition to spastic paraplegia phenotype. PMID:32623594
• Frontiers in neuroscience • 2019 • Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila. PMID:31780887

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